Human T cell leukemia virus type I (HTLV-I) is an RNA tumor virus identified as a causative agent of adult T cell leukemia and shown to be associated with several neurological and chronic disorders. An estimated 10 to 20 million people are infected by HTLV-I worldwide. Of these only a small percentage have symptomatic disease, the majority of infections are silent. The mechanisms of the development and pathogenesis of HTLV-I associated diseases remain unknown. This project is focused on understanding the pathogenic mechanisms of HTLV-I by means of studies on the interaction between HTLV-I viral products and various cellular molecules. These studies utilize virus that is known to cause disease in rabbits compared to those that cause asymptomatic infection. Current investigations focus on two distinct HTLV-I infected rabbit cell lines: RH/K30 which mediates asymptomatic infection and RH/K34 which causes acute leukemia-like diseases. These lines have been characterized at the level of cell surface molecule, virus structure and a molecular clone of the virus from each line has been obtained. These studies have revealed only minor differences in the lines. Most recent studies emphasize cellular signaling pathways that regulate cell proliferation, differentiation and programmed cell death. Initial experiments examined the status of tyrosine phosphorylation of several key proteins in RH/K30 and RH/K34.. Our data clearly indicate that there is constitutive tyrosine phosporylation of proto-oncogene products Vav and c-CBl, and of the Janus kinase Tyk2 and STAT3 proteins only in the leukemogenic cell line RH/K34, but not in RH/K30. In RH/K30 it was possible to induce activation of the Tyk2 pathway with IL-10 (RH/K34 produces IL-10). In addition, use of HTLV-I molecular clones reveals that the genes in HTLV-I pX region influence tyrosine phosporylation of Vav. These results suggest that constitutive activation of certain signaling pathway may be associated with pathogenesis of HTLV-I infected cells. - cell signaling, molecular pathogenesis of HTLV-I, Adult T-cell leukemia, human retroviruses